Progression of Retinopathy in Insulin-Treated Type 2 Diabetic Patients:

A total of 45 consecutive, orally treated type 2 diabetic patients <75 years of age were included in the study when they, due to unsatisfactory metabolic control, were referred to the Diabetic Day Care Unit at the Department of Endocrinology in Malmö, Sweden, to be changed to insulin therapy (Table 1). Patients with severe concomitant diseases preventing follow-up, patients with severe nonproliferative retinopathy or proliferative retinopathy, and patients with cataracts, making retinal photography impossible, were excluded from the study.

The patients were examined at baseline, before the introduction of insulin therapy, and at follow-up after 1, 3, 6, 12, 24, and 36 months. Fundus photography including visual acuity testing was performed, and blood samples for HbA_1c and IGF-1 were collected during all examinations. At baseline, a simple neurological examination was performed; tendon reflexes and vibratory sensory thresholds were assessed using a biothesiometer at the ankle region (Bio-thesiometer; BioMedical Instrument, Newbury, OH). Patients were asked about smoking and current antihypertensive treatment. Blood pressure was measured in each patient in the supine position after 5 min rest. Hypertension was considered present if the patient was taking antihypertensive drugs or if blood pressure was >160/95 mmHg. Urinary albumin excretion rate was measured at baseline and after 12, 24, and 36 months. The study was approved by the Ethics Committee at the University of Lund, Sweden. Informed consent was obtained from all participating patients.

HbA_1c was measured by ion exchange chromatography (19); the reference interval was <5.3%. Urinary albumin was measured by rate immunonephelometry (Beckman ARRAY instrument; Beckman Instruments, Fullerton, CA). Microalbuminuria was defined as an albumin excretion of 20–200 μg/min. Fasting plasma C-peptide was measured by radioimmunoassay (20). IGF-1 was measured by an immunometric assay kit (IGF-1 IRMA; Nichols Institute Diagnostics, San Juan Capistrano, CA) according to the instructions of the manufacturer. The intra- and interassay coefficients of variation were 5 and 15%, respectively, at the level 60 μg/l. The detection limit was 6 μg/l.

Stereo color fundus photographs of the seven standard fields were taken during pharmacological mydriasis, at an angle of 30°, with a Topcon TRC-50 VT fundus camera (Tokyo Optical, Tokyo). The alternative classification of the Wisconsin Epidemiologic Study of Diabetic Retinopathy was used to define the retinopathy level (21,22). This classification provides an overall retinopathy scale: level 10 represents no retinopathy, levels 21–51 represent nonproliferative diabetic retinopathy of increasing severity, and levels 60+ represent all forms of PDR with and without laser treatment. The patient’s retinopathy level was derived by giving the eye with the higher level a greater weight. This scheme provides an 11-step scale: 10, 21/10, 21/21, 31/<31, 31/31, 41/<41, 41/41, 51/<51, 51/51, 60+/<60+, 60+/60+ (22). Thereafter, the retinopathy levels were divided into four groups; no diabetic retinopathy (level 10), mild retinopathy (levels 21/10−31/31), moderate nonproliferative retinopathy (levels 41/<41−51/<51), and severe nonproliferative or proliferative retinopathy (levels 51/51−60+/60+).

Macular edema was defined as the presence of hard exudates and/or retinal thickening within one disc diameter of the center of the macula in at least one eye. Macular treatment was defined as focal laser treatment in at least one eye. Proliferative retinopathy and macular edema were treated according to established guidelines.

Photographs were viewed against light boards using Donaldson’s stereo viewer (magnification ×5; G. J. Davco, Holbrook, MA) and assessed by an independent grader with extensive experience with this classification. The grader had no knowledge of the patients’ clinical data. No patients were excluded from the study because of media opacities.

For the testing of visual acuity, the Monoyer charts (0.1–1.0 decimal scale) were used. The visual acuity of the best eye was reported.

The group with progression ≥3 levels was compared with the group with progression ≤2 levels. A progression of ≥3 levels was considered a clinically significant deterioration.

Change in severity of retinopathy was assessed for the association with HbA_1c and IGF-1.

The statistical analyses were performed with the statistical software SPSS for Windows (SPSS, Chicago, IL). Friedman and Wilcoxon signed-rank tests were used to analyze changes between repeated measurements. The area under the curve was estimated for each patient and variable that was measured serially (23). When analyzing differences between variables in two independent groups, Student’s t test, Mann-Whitney U test, χ² test, and Fisher’s exact test were used. Multiple regression analysis was used to assess the influence of HbA_1c, IGF-1, and retinopathy at baseline on progression ≥3 levels and was performed with all variables entered in a single step. Significance was considered for P ≤ 0.05. Results were given with 95% CI; data are presented as means ± SD.

Three patients died during the 3-year follow-up; 42 patients completed the study and remained on insulin therapy after 3 years. At baseline, 21 of 42 patients (50%) showed no retinopathy, whereas among the remaining 21 patients, 16 had mild retinopathy and 5 had moderate retinopathy (Tables 1 and 2). After 3 years, the level of retinopathy had progressed in 20 of 42 patients (48%). The progression affected all levels of retinopathy, i.e., from no retinopathy to moderate nonproliferative diabetic retinopathy (Table 2). At 36 months, three patients had progressed to PDR and eight patients (five at inclusion) had been treated for macular edema.

When comparing baseline values with average values during follow-up in the whole patient group (area under the curve divided by 36 months), HbA_1c and IGF-1 were significantly reduced (Fig. 1) (P < 0.01). The decrease in HbA_1c levels occurred rapidly (within 3 months) after the initiation of insulin therapy, whereas IGF-1 levels decreased gradually (maximal after 36 months). The level of IGF-1 was not related to age. The group of patients with progression ≥3 levels (n = 11) and the group of patients with progression ≤2 levels (n = 31) had significant reduction in HbA_1c values, with no significant difference between the groups, whereas the IGF-1 levels were significantly reduced only in the group with less progression (P < 0.01) (Table 3). In agreement, a higher average IGF-1 (per 10 units) at 36 months was significantly associated with retinopathy progression ≥3 levels in a logistic regression analysis (Table 4). When average HbA_1c and IGF-1 were entered into the analysis, this association disappeared. There were no relationships between the degree of retinopathy or other clinical features at entry and the progression by ≥3 levels (Table 1). Macular edema developed in two patients in the group with little or no progression and in one patient in the group with progression ≥3 levels (NS). Visual acuity of the best eye was similar in both groups at baseline (1.0 [95% CI 0.5–1.0]) but deteriorated significantly in the group with most severe progression (0.6 [0.5–1.0]) during the 3 years of observation (P = 0.02). The insulin doses per kilogram body weight were equal in both groups (measured at 24 months). The frequency of albuminuria (≥20 μg/min) was higher at 36 months than at baseline (P = 0.04), but there was no difference between the groups (Table 3). Four patients underwent cataract surgery during follow-up (no differences between groups), and one patient with progression ≥3 levels underwent vitrectomy of both eyes because of recurrent vitreous hemorrhages.

Several of the patients in our study had progression of retinopathy. Of the 42 patients with mild to moderate retinopathy, four patients required panretinal laser treatment and one patient underwent vitrectomy. In the previous 2-year follow-up of the current patient group, we found a relationship between decreased HbA_1c level and retinopathy progression (9). Such a relationship was not seen after 3 years. A lack of decrement in IGF-1 3 years after the start of insulin therapy was associated with progression of retinopathy. Therefore, it seems that an initial improvement in glycemic control may have favored the early progression of retinopathy, and that factors associated with high IGF-1 concentrations may be related to later-occurring progression. The higher IGF-1 value may be a marker of the improved glycemic control. In keeping with our observation of decrements in IGF-1 levels during insulin therapy, IGF-1 levels are lower in insulin-treated type 2 diabetic patients than in those on other therapies (24). A decrease in IGF-1 in type 2 diabetic patients may depend on reduced endogenous insulin production secondary to systemic insulin injections (14). This hypothesis could not be tested in our study; endogenous insulin secretion as C-peptide was only measured before the start of insulin therapy.

There is experimental evidence of an influence of GH and IGF-1 on progression of retinopathy. Retinal microvascular cells have receptors for IGF-1, and IGF-1 induces the release of plasminogen activator and increases DNA synthesis in retinal endothelium (25). Inhibitory action of the GH suppressor ocreotide on human retinal endothelial cells’ proliferation and DNA synthesis has been shown in vitro (26). According to Smith et al. (27), an IGF-1 receptor antagonist suppresses retinal neovasularization. An interaction between IGF-1 and the IGF-1 receptor is necessary for induction of neovascularization by vascular endothelial growth factor (28).

In conclusion, in type 2 diabetic patients treated with oral agents, within a few months after initiation of insulin therapy, glycemic control, as reflected by HbA_1c, improved and persisted for at least 3 years. There was, however, a tendency toward increased glycemia after 2–3 years. In contrast to HbA_1c, IGF-1 was continuously reduced; the lowest values were recorded 3 years after initiation of insulin therapy. We found a relationship between progression of retinopathy and a higher IGF-1 value at 3 years. Our study is small but raises questions about the relationship between retinopathy, hyperglycemia, insulin therapy, and IGF-1.

This study was supported by the Gorthon and Zoéga Foundations (Helsingborg), the Järnhardt Foundation, the Swedish Diabetes Association, the Lundström Foundation, the Novo-Nordic Foundation, and research funds of Malmö University Hospital, the County of Malmöhus, and the Swedish Medical Research Council (Grant 7507).

We thank Jonas Ranstam, PhD, for statistical supervision; Eva Steffert for grading of photographs; and Janet Parmvi for valuable assistance.